5’-Deoxy-5’-Methylthioadenosine: Novel Metabolic and Physiological Aspects

This chapter discusses some of the recent achievements on methylthioadenosine (MTA) metabolism, with particular emphasis towards the molecular properties of the enzymes involved in the control of the cellular content of the molecule. MTA is also produced in eukaryotes during the biosynthesis of diphthamide (2-[3-carboxyamido-3-(trimethylammonio)propyl]histidine), a posttranslational modified amino-acid identified in the elongation factor. The major biochemical differences between normal and mutant cells are the higher level of AdoMet and AdoMet synthase activity occurring in the MTA-resistant clones; this metabolic response could be envisioned as a sort of mechanism of cell protection. Polyamine depletion, caused by inhibition of the spermidine and spermine synthase, has been proposed by several authors as a major mechanism of MTA antiproliferative action. Nevertheless, the observation that the addition of polyamines does not reverse the cytostatic effect of the thioether casts serious doubts upon this mechanism.